Polymer based radionuclide containing particulate material

ABSTRACT

The invention relates to a particulate material having a diameter in the range of from 5 to 200 microns comprising polymeric matrix and stably incorporated radionuclide, processes for its production and a method of radiation therapy utilising the particulate material.

This application is a continuation of application Ser. No. 11/743,530,filed May 2, 2007, which is a continuation of Ser. No. 10/173,496, filedJun. 17, 2002, which is a continuation of PCT/AU01/01370, filed Oct. 25,2001, which applications are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

This invention relates to a particulate material that comprises apolymer, particularly a polymer and a radionuclide, to a method for theproduction thereof, and to methods for the use of this particulatematerial.

In on particular aspect, this invention relates to microspheres whichcomprise a polymer and a radionuclide such as radioactive yttrium, andto the use of these microspheres in the treatment of cancer in humansand other mammals.

The particulate material of this invention is designed to beadministered into the arterial blood supply of an organ to be treated,whereby it becomes entrapped in the small blood vessels of target organand irradiates it. An alternate form of administration is to inject thepolymer based particulate material directly into the target organ or asolid tumour to be treated.

The particulate material of the present invention therefore has utilityin the treatment of various forms of cancer and tumours, butparticularly in the treatment of primary and secondary cancer of theliver and the brain. It is to be understood that the particulatematerial of the invention is not limited to radioactive microspheres,but may be extended to other radioactive polymeric particles which aresuitable for use in the treatment methods described herein.

BACKGROUND OF THE INVENTION

Many previous attempts have been made to locally administer radioactivematerials to patients with cancer as a form of therapy. In some ofthese, the radioactive materials have been incorporated into smallparticles, seeds, wires and similar related configurations that can bedirectly implanted into the cancer. When radioactive particles areadministered into the blood supply of the target organ, the techniquehas become known as Selective Internal Radiation Therapy (SIRT).Generally, the main form of application of SIRT has been its use totreat cancers in the liver.

There are many potential advantages of SIRT over conventional, externalbeam radiotherapy. Firstly, the radiation is delivered preferentially tothe cancer within the target organ. Secondly, the radiation is slowlyand continually delivered as the radionuclide decays. Thirdly, bymanipulating the arterial blood supply with vasoactive substances (suchas Angiotensin-2), it is possible to enhance the percentage ofradioactive particles that go to the cancerous part of the organ, asopposed to the healthy normal tissues. This has the effect ofpreferentially increasing the radiation dose to the cancer whilemaintaining the radiation dose to the normal tissues at a lower level(Burton, M. A. et al.; Effect of Angiotensin-2 on blood flow in thetransplanted sheep squamous cell carcinoma. Europ. J. Cancer Clin.Oncol. 1988, 24(8):1373-1376).

When microspheres or other small particles are administered into thearterial blood supply of a target organ, it is desirable to have them ofa size, shape and density that results in the optimal homogeneousdistribution within the target organ. If the microspheres or smallparticles do not distribute evenly, and as a function of the absolutearterial blood flow, then they may accumulate in excessive numbers insome areas and cause focal areas of excessive radiation. It has beenshown that microspheres of approximately 25-50 micron in diameter havethe best distribution characteristics when administered into thearterial circulation of the liver (Meade, V. et al.; Distribution ofdifferent sized microspheres in experimental hepatic tumours. Europ. J.Cancer & Clin. Oncol. 1987, 23:23-41).

If the particles are too dense or heavy, then they will not distributeevenly in the target organ and will accumulate in excessiveconcentrations in areas that do not contain the cancer. It has beenshown that solid, heavy microspheres distribute poorly within theparenchyma of the liver when injected into the arterial supply of theliver. This, in turn, decreases the effective radiation reaching thecancer in the target organ, which decreases the ability of theradioactive microspheres to kill the tumour cells. In contrast, lightermicrospheres with a specific gravity of the order of 2.0 distribute wellwithin the liver (Burton, M. A. et al.; Selective InternationalRadiation Therapy; Distribution of radiation in the liver. Europ. J.Cancer Clin. Oncol. 1989, 25:1487-1491).

For radioactive particulate material to be used successfully for thetreatment of cancer, the radiation emitted should be of high energy andshort range. This ensures that the energy emitted will be deposited intothe tissues immediately around the particulate material and not intotissues which are not the target of the radiation treatment. In thistreatment mode, it is desirable to have high energy but shortpenetration beta-radiation which will confine the radiation effects tothe immediate vicinity of the particulate material. There are manyradionuclides that can be incorporated into microspheres that can beused for SIRT. Of particular suitability for use in this form oftreatment is the unstable isotope of yttrium (Y-90). Yttrium-90 decayswith a half life of 64 hours, while emitting a high energy pure betaradiation. However, other radionuclides may also be used in place ofyttrium-90 of which the isotopes of holmium, samarium, iodine, iridium,phosphorus, rhenium are some examples.

Ceramic particles have been produced that are either coated with orcontain radionuclides. However, the presence of other radioactivesubstances that are not required for the radiation treatment of thetarget tissue, has then unwanted and deleterious radiation effects mayoccur. It is therefore desirable to have particulate material of such acomposition that it only contains the single desired radionuclide.

In the earliest clinical use of yttrium-90 containing microspheres, theyttrium was incorporated into a polymeric matrix that was formulatedinto microspheres. While these microspheres were of an appropriatedensity to ensure good distribution characteristics in the liver, therewere several instances in which the yttrium-90 leached from themicrospheres and caused inappropriate radiation of other tissues.Attempts to incorporate other radionuclides such as holmium into resinor polymer based materials have resulted in leaching of the radionuclideand this has resulted in severe consequences for the patients that havebeen treated with the product.

In one attempt to overcome the problem of leaching, a radioactivemicrosphere comprising a biologically compatible glass materialcontaining a beta- or gamma-radiation emitting radioisotope such asyttrium-90 distributed throughout the glass, has been developed(International Patent Publication No. WO 86/03124). These microspheresare solid glass and contain the element yttrium-89 that can be activatedto the radionuclide yttrium-90 by placing the microspheres in a neutronbeam. These glass microspheres have several disadvantages includingbeing of a higher specific gravity than is desirable and containingother elements such as alumina and silica which are activated toundesirable radionuclides when placed in a neutron beam.

Another approach has been focussed on the use of small hollow orcup-shaped ceramic particles or microspheres, wherein the ceramic basematerial consists or comprises yttria or the like (International PatentPublication No. WO 95/19841). These microspheres were developed toovercome the problem of high density associated with the solid glassmicrospheres described in International Patent Publication No.WO86/03124.

SUMMARY OF THE INVENTION

In one aspect the present invention provides a particulate materialhaving a diameter in the range of from 5 to 200 microns comprising apolymeric matrix and a stably incorporated radionuclide.

In another aspect, the invention provides a process for the productionof a particulate material having a diameter in the range of from 5 to200 microns comprising the step of combining a polymeric matrix and aradionuclide for a time and under conditions sufficient to stablyincorporate the radionuclide in the matrix to produce a particulatematerial having a diameter in the range of from 5 to 200 microns.

In another aspect, the present invention provides a method of radiationtherapy of a patient, which comprises administration to the patient of aparticulate material having a diameter in the range of from 5 to 200microns comprising a polymeric matrix and a stably incorporatedradionuclide.

The present invention also provides for the use of particulate materialhaving a diameter in the range of from 5 to 200 microns comprising apolymeric matrix and a stably incorporated radionuclide in the radiationtherapy of a patient.

BRIEF DESCRIPTION OF THE DRAWINGS

Further objected and advantages of the present invention will be morefully appreciated from a reading of the detailed description whenconsidered with the accompanying drawing wherein:

FIG. 1 depicts pH results when the phosphate concentration the solutionused to precipitate the radionuclide was varied; FIG. 1 further shows pHresults measured when a microsphere suspension is washed with aphosphate buffer having pH of 7.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, references to the radionuclide being stably incorporatedinto particulate material or polymeric matrix are to be understood asreferring to incorporation of the radionuclide so that it does notsubstantially leach out of the particulate material under physiologicalconditions such as in the patient or in storage. In a preferredembodiment the radionuclide is incorporated by precipitation into apolymeric matrix.

The leaching of radionuclides from the polymeric matrix can causenon-specific radiation of the patient and damage surrounding tissue.Preferably the amount of leaching is less than 5%, more preferably lessthan 4%, 3%, 2%, 1% or 0.4%. One method of assessing leaching is byadjusting a sample to pH 7.0 and agitating in a water bath at 37° C. for20 minutes. A 100 μL sample is counted for beta emission in aGeiger-Müller counter. Another representative 100 μL sample is filteredthrough a 0.22 μm filter and the filtrate counted for beta emission inthe Geiger-Müller counter. The percent unbound radionuclide iscalculated by:

${\frac{FiltrateCount}{SampleCount} \times 100} = {\% \mspace{14mu} {UnboundRadionuclide}}$

The radionuclide can be stably incorporated into the polymeric matrix byprecipitating it as an insoluble salt. Where the radionuclide used isyttrium-90 the yttrium is preferably precipitated as a phosphate salt.However the present invention also extends to precipitation of theradionuclide as other insoluble salts including, for example, carbonateand bicarbonate salts. The radionuclide which is incorporated into thepolymeric matrix in accordance with the present invention is preferablyyttrium-90, but may also be any other suitable radionuclide which can beprecipitated in solution, of which the isotopes of holmium, samarium,iodine, phosphorous, iridium and rhenium are some examples.

In a preferred embodiment the particulate material is a microsphere. Theterm microsphere is used in this specification as an example of aparticulate material, it is not intended to limit the invention tomicrospheres, as the person skilled in the art will appreciate that theshape of the particulate material while preferably without sharp edgesor points that could damage the patients arteries or catch in unintendedlocations, is not limited to spheres. Nor should the term microsphere belimited to spheres. Preferably the particulate material is substantiallyspherical, but need not be regular or symmetrical in shape.

In a preferred embodiment the polymeric matrix is partially crosslinked. Preferably there is about 1% to about 20% cross linking,preferably about 2% to 10% cross linking and more preferably about 4%cross linking.

In particular, the present invention provides a particulate material asdescribed above in which the polymeric matrix is an ion exchange resin,particularly a cation exchange resin. Preferably the ion exchange resincomprises a partially cross linked aliphatic polymer, includingpolystyrene. One particularly preferred cation exchange resin is thestyrene/divinylbenzene copolymer resin commercially available under thetrade name Aminex 50W-X4 (Biorad, Hercules, Calif.). However, there aremany other commercially available cation exchange resins which aresuitable.

When small particles are administered into the arterial blood supply ofa target organ, it is desirable to have them of a size, shape anddensity that results in the optimal homogeneous distribution within thetarget organ. If the small particles do not distribute evenly then theymay accumulate in excessive numbers in some areas and cause focal areasof excessive radiation. The particulate material is preferably lowdensity, more particularly a density below 3.0 g/cc, even morepreferably below 2.8 g/cc, 2.5 g/cc, 2.3 g/cc, 2.2 g/cc or 2.0 g/cc. Theideal particle for injection into the blood stream would have a verynarrow size range with a SD of less than 5%, so as to assist in evendistribution of the microspheres within the target organ, particularlywithin the liver and would be sized in the range 5-200 micron preferably15-100 micron and preferably 20-50 micron, and most preferably 30-35micron.

It is also desirable to have the particulate material manufactured sothat the suspending solution has a pH less than 9. If the pH is greaterthan 9 then this may result in irritation of the blood vessels when thesuspension is injected into the artery or target organ. Preferably thepH is less than 8.5 or 8.0 and more preferably less than 7.5.

The present invention particularly provides a method for the productionof a radioactive particulate material comprising a polymeric matrix asdescribed above, characterised by the steps of:

(i) absorbing a radionuclide onto an ion-exchange resin particulatematerial having a diameter in the range of 20 to 50 microns and aspecific gravity of less than 2.5; and(ii) precipitating the radionuclide as an insoluble salt to stablyincorporate the radionuclide into the particulate material.

In a preferred embodiment, the method of the present invention iscarried out by firstly irradiating yttria (yttrium oxide) in a neutronbeam to activate yttria to the isotope yttrium-90. The yttrium-90 oxideis then solubilised, for example as yttrium-90 sulphate solution. Theion exchange resin is preferably provided in the form of an aqueousslurry of microspheres of ion exchange resin having a particle size 30to 35 microns, and the yttrium-90 sulphate solution is added to theslurry to absorb the yttrium-90 into the ion exchange resinmicrospheres. Subsequently, the yttrium-90 is precipitated as aphosphate salt, for example by addition of tri-sodium phosphatesolution, to stably incorporate the yttrium-90 into the microspheres.The particulate material may be combined with a solution of theradionuclide or the salt of the radionuclide may be combined with theparticulate matter, in a solution suitable for solubilising theradionuclide.

Alternate sources of yttrium-90 may be used in the production of thesemicrospheres. For example, a highly pure source of yttrium-90 may beobtained by extracting yttrium-90 from a parent nuclide and using thisextracted yttrium-90 as the source of the soluble yttrium salt that isthen incorporated into the polymeric matrix of the microspheres.

In order to decrease the pH of the suspension containing themicrospheres for injection into patients the microspheres may be washedto remove any un-precipitated or loosely adherent radionuclide. Thepresent invention provides a suspension of the required pH byprecipitating the yttrium with a tri-sodium phosphate solution at aconcentration containing at least a three-fold excess of phosphate ion,but not exceeding a 30-fold excess of phosphate ion, and then washingthe microspheres with de-ionised water. Another approach which ensuresthat the pH of the microsphere suspension is in the desired range is towash the resin with a phosphate buffer solution of the desired pH.

The present invention also provides a method of radiation therapy of ahuman or other mammalian patient that comprises administration to thepatient of particulate material as described above. The person skilledin the art will appreciate the administration may be by any suitablemeans and preferably by delivery to the relevant artery. For example intreating liver cancer, administration is preferably by laparotomy toexpose the hepatic artery or by insertion of a catheter into the hepaticartery via the femoral, or brachial artery. Pre or co-administration ofanother agent may prepare the tumour for receipt of the particulatematerial, for example a vasoactive substance, such as angiotension-2 toredirect arterial blood flow into the tumour. Delivery of theparticulate matter may be by single or multiple doses, until the desiredlevel of radiation is reached.

Throughout this specification, unless the context requires otherwise,the word “comprise”, and or variations such as “comprises” or“comprising”, will be understood to imply the inclusion of a statedinteger or step or group of integers or steps but not the exclusion ofany other integer or step or group of integers or steps.

Further features of the present invention are more fully described inthe following Examples. It is to be understood, however, that thisdetailed description is included solely for the purposes of exemplifyingthe present invention, and should not be understood in any way as arestriction on the broad description of the invention as set out above.

Example 1

Yttrium (90Y) labelled microspheres are made in the form of a sterile,pyrogen free suspension of resin beads labelled with yttrium (90Y)phosphate. The resin beads consist of sulphuric acid groups attached toa styrene divinylbenzene copolymer lattice.

Yttrium oxide is irradiated to produce yttrium-90 from the nuclearreaction Y-89 (n, γ) Y-90. Yttrium-90 has a half life of 64 hours. Theyttrium (90Y) oxide is then dissolved in 0.1M sulphuric acid with gentleheating and stirring to form a clear, colourless solution of yttrium(90Y) sulphate.

Symmetrical microspheres of ion exchange resin (Aminex 50W-X4 cationexchange resin; supplied by ‘Bio-Rad Cat #1474313’) with a diameter ofapproximately 30 to 35 microns are added to water (Water for InjectionsBP) to form a slurry that is then transferred into a reaction vessel.Yttrium (90Y) sulphate solution is added to the reaction vessel and themixture stirred at a speed sufficient to ensure homogeneity to absorbthe yttrium (90Y) solution into the resin-based microspheres. Tri-sodiumphosphate solution (1.25% w/v) is then added to the reaction vessel withfurther stirring to precipitate the radionuclide as yttrium (90Y)phosphate.

The microspheres are then washed with a phosphate buffer solution untilthe pH of the wash solution is less than 9 and preferable less than 8.5.Following washing of the microspheres with water (Water for InjectionBP), the microspheres are resuspended and diluted (if necessary) withwater (Water for Injections BP) to give a light brown suspension havingan activity of 3000 MBq

10%.

The resin-based yttrium microspheres produced by the above method have0.01-0.4% unbound or unprecipitated 90Y when tested in the followingleaching test:

A 5 μL sample is diluted with water to 5 mL, adjusted to pH 7.0 andagitated in a water bath at 37° C. for 20 minutes. A 100 μL sample iscounted for beta emission in a Geiger-Müller counter. Anotherrepresentative 100 μL sample is filtered through a 0.22 μm filter andthe filtrate counted for beta emission in the Geiger-Müller counter. Thepercent unbound 90Y is calculated by:

${\frac{FiltrateCount}{SampleCount} \times 100} = {\% \mspace{14mu} {{Unbound}\;}^{90}Y}$

Example 2

The effect of phosphate concentration in the precipitation solution, andthe effects of washing with phosphate buffer on the pH of a microspheresuspension are shown in the attached FIG. 1 which sets out the resultsof a number of experiments.

Example 3

The technique of Selective Internal Radiation Therapy (SIRT) has beendescribed above. It involves either a laparotomy to expose the hepaticarterial circulation or the insertion of a catheter into the hepaticartery via the femoral, brachial or other suitable artery. This may befollowed by the infusion of Angiotensin-2 into the hepatic artery toredirect arterial blood to flow into the metastatic tumour component ofthe liver and away from the normal parenchyma. This is followed byembolisation of resin based yttrium-90 containing microspheres (producedin accordance with Example 1) into the arterial circulation so that theybecome lodged in the microcirculation of the tumour. Repeated injectionsof microspheres are made until the desired radiation level in the normalliver parenchyma is reached. By way of example, an amount of yttrium-90activity that will result in an inferred radiation dose to the normalliver of approximately 80 Gy may be delivered. Because the radiationfrom SIRT is delivered as a series of discrete point sources, the doseof 80 Gy is an average dose with many normal liver parenchymal cellsreceiving much less than that dose.

The measurement of tumour response by objective parameters includingreduction in tumour volume and serial estimations of serumcarcino-embryonic antigen (CEA) levels, is an acceptable index of theability of the treatment to alter the biological behaviour of thetumour.

1. A particulate material having a diameter in the range of from 5 to200 microns comprising a polymeric matrix and stably incorporatedradionuclide.
 2. The particulate material according to claim 1 whereinthe radionuclide is incorporated by precipitation.
 3. The particulatematerial according to claim 1 wherein the polymeric matrix is partiallycross linked.
 4. The particulate material according to claim 3 whereinthe polymeric matrix comprises from about 1% to about 20% cross linking.5. The particulate material according to claim 4 wherein the polymericmatrix comprises about 4% cross linking.
 6. The particulate materialaccording to claim 1 wherein the polymeric matrix is an ion exchangeresin.
 7. The particulate material according to claim 6 wherein thepolymeric matrix is a cation exchange resin.
 8. The particulate materialaccording to claim 6 wherein the ion exchange resin comprises apartially cross linked aliphatic polymer.
 9. The particulate materialaccording to claim 6 wherein the ion exchange resin comprises apartially cross linked polystyrene.
 10. The particulate materialaccording to claim 9 wherein the ion exchange resin comprisespolystyrene partially cross linked with divinyl benzene.
 11. Theparticulate material according to claim 1, wherein the radionuclide isan isotope of yttrium, holmium, samarium, iodine, phosphorus, iridium orrhenium.
 12. The particulate material according to claim 1, wherein theradionuclide is yttrium-90.
 13. The particulate material according toclaim 1 being a microsphere.
 14. A particulate material having adiameter in the range of from 30 to 35 microns comprising a copolymercomprised of styrene and divinyl benzene and precipitated yttrium-90.15. A process for the production of a particulate material according toclaim 1 comprising the step of combining a polymeric matrix and aradionuclide in solution for a time and under conditions sufficient tostably incorporate the radionuclide in the matrix to produce aparticulate material having a diameter in the range of from 5 to 200microns.
 16. A process according to claim 15 wherein the radionuclide isstably incorporated by precipitation into the polymeric matrix.
 17. Aprocess according to claim 15 wherein the radionuclide is yttrium-90.18. A method of radiation therapy of a patient, which comprisesadministration to the patient of a particulate material having adiameter in the range of from 5 to 200 microns comprising a polymericmatrix and a stably incorporated radionuclide.
 19. A method according toclaim 18 wherein the radionuclide is yttrium-90.
 20. A method accordingto claim 18 wherein the radiation therapy comprises treatment of aprimary or secondary liver cancer.
 21. Use of particulate materialhaving a diameter in the range of from 5 to 200 microns comprising apolymeric matrix and a stably incorporated radionuclide in radiationtherapy of a patient.
 22. Use according to claim 21 wherein theradionuclide is yttrium-90.
 23. Use according to claim 21 wherein theradiation therapy comprises treatment of a primary or secondary livercancer.